Predisposition to late-onset obesity in GIRK4 knockout mice
Predisposition to late-onset obesity in GIRK4 knockout mice
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DOI：
10.1073/pnas.0803261105
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发表时间：
2008-06-10
影响因子：
11.1
通讯作者：
Wickman, Kevin
中科院分区：
文献类型：
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作者：
Perry, Cydne A.;Pravetoni, Marco;Wickman, Kevin
G 蛋白门控内向整流钾 (GIRK/Kir3) 通道介导许多神经递质对兴奋细胞的抑制作用。已鉴定出四个 Girk 基因 (Girk1-4)。尽管 GIRK4 与心脏 GIRK 通道相关，但已在少数神经元群体中检测到了 Girk4 表达。在这里，我们使用在Girk4基因启动子控制下表达增强型绿色荧光蛋白（EGFP）的转基因小鼠来阐明Girk4在大脑中的表达模式。尽管在某些区域存在明显的 EGFP 阳性神经元小亚群，但在下丘脑中观察到明显的标记。 EGFP 表达在腹内侧核、室旁核和弓状核以及与能量稳态有关的神经元群中最为明显。与含有 GIRK4 的通道对能量平衡的贡献一致，Girk4 敲除 (-/-) 小鼠易患迟发性肥胖。到 9 个月时，Girk4(-/-) 小鼠比野生型对照小鼠重约 25%，这种差异归因于体内脂肪较多。在超重之前，Girk4(-/-) 小鼠表现出摄入更多食物的倾向，并且在操作性任务中更倾向于寻找食物。尽管静息心率和核心体温升高，Girk4(-/-) 小鼠也表现出净能量消耗减少。这些数据表明含有 GIRK4 的通道对能量稳态和体重至关重要。
G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels mediate the inhibitory effects of many neurotransmitters on excitable cells. Four Girk genes have been identified (Girk1-4). Whereas GIRK4 is associated with the cardiac GIRK channel, Girk4 expression has been detected in a few neuron populations. Here, we used a transgenic mouse expressing enhanced green fluorescent protein (EGFP) under the control of the Girk4 gene promoter to clarify the expression pattern of Girk4 in the brain. Although small subsets of EGFP-positive neurons were evident in some areas, prominent labeling was seen in the hypothalamus. EGFP expression was most pronounced in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis. Consistent with a contribution of GIRK4-containing channels to energy balance, Girk4 knockout (-/-) mice were predisposed to late-onset obesity. By 9 months, Girk4(-/-) mice were approximate to 25% heavier than wild-type controls, a difference attributed to greater body fat. Before the development of overweight, Girk4(-/-) mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4(-/-) mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicate GIRK4-containing channels in signaling crucial to energy homeostasis and body weight.